Prostaglandins play a major role in the inflammation process and the inhibition of prostaglandin production, especially production of PGG.sub.2, PGH.sub.2 and PGE.sub.2, has been a common target of antiinflammatory drug discovery. However, common non-steroidal antiinflammatory drugs (NSAIDs) that are active in reducing the prostaglandin-induced pain and swelling associated with the inflammation process are also active in affecting other prostaglandin-regulated processes not associated with the inflammation process. Thus, use of high doses of most common NSAIDs can produce severe side effects, including life threatening ulcers, that limit their therapeutic potential. An alternative to NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long term therapy is involved.
Previous NSAIDs have been found to prevent the production of prostaglandins by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway, including the enzyme cyclooxygenase (COX). The recent discovery of an inducible enzyme associated with inflammation (named "cyclooxygenase-2 (COX-2)" or "prostaglandin G/H synthase II") provides a viable target of inhibition which more effectively reduces inflammation and produces fewer and less drastic side effects.
The novel compounds described herein are such safe and also effective antiinflammatory agents. The invention compounds are found to show usefulness in vivo as antiinflammatory agents with minimal side effects. The compounds described herein preferably selectively inhibit cyclooxygenase-2 over cyclooxygenase-1.
Substituted pyrazoles having antiinflammatory activity are described in copending applications 08/160,594 and 08/160,553.
U.S. Pat. No. 3,940,418 to R. Hamilton describes tricyclic 4,5-dihydrobenzg!indazole-3-carboxylic acids as antiinflammatory agents.
U.S. Pat. No. 4,803,193 to Kanda et al, describes spiro3-alkyl-1-aryl1!benzopyrano4,3-c!pyrazole-4(1H),9'-9H!fluorenes as heat sensitive recording matertials.
V. Colota et al (J.Med.Chem., 33, 2646 (1991)) describe tricyclic heteroaramatic systems, including 1-aryl-pyrazolo4,5-c!quinolin-4-ones, 1-aryl-pyrazolo4,5-c!1,8!naphthyridin-4-ones and 1-aryl-1!benzopyrano3,4-d!pyrazol-4-ones for CNS applications. F. Melani et al J.Med.Chem., 29, 291 (1986) also describe 1-phenyl-pyrazolo4,5-c!quinolines for CNS applications.
U.S. Pat. Nos. 4,816,467 and 5,206,258 to Doria et al describe (2-cyano-3-(1,4-dihydro)-1-phenyl-1!benzothiopyrano4,3-c!pyrazol-3-yl)-3 -oxo-propanamides as immunomodulators. G. Doria et al (Farmaco, 46, 843 (1991)) also describe the immunomodulating activity of pyrazolylpropanamides, and specifically ethyl 1-(4-fluorophenyl)-1,4-dihydro-1!benzothiopyrano4,3-c!pyrazole!-3-carbo xylate. British patent 2,227,741 describes related benzopyrano4,3-c!pyrazoles and benzothiopyrano 4,3-c!pyrazoles. European application No. 347,773 similarly describes such fused pyrazole compounds, and specifically .alpha.-cyano-N,1-bis(4-fluorophenyl)-.beta.-oxo-1H-1!benzothieno3,2-c!p yrazole-3-propanamide. U.S. Pat. No. 5,260,328 to Doria et al describes 2-cyano-3-(1,4-dihydro)-1-phenyl-1!benzothiopyrano4,3-c!pyrazol-3-yl)-3- oxo-propanamides for the treatment of rheumatoid arthritis.
U.S. Pat. No. 4,678,499 to Pasteris et al describes 1-aryl-indenopyrazol-4-one-5-sulfonamides as having herbicidal activity. Specifically, 1-phenylindenopyrazol-4-one-5-sulfonamide and 1,4-dihydro-N-(4-methoxy-6-methyl-2-pyrimidinyl)amino!carbonyl!-3-methyl -1-(4-(methylsulfonyl)phenyl!-4-oxo-indeno1,2-c!pyrazole-5-sulfonamide are described.
The invention's benzopyranopyrazolyl derivatives are found to show usefulness in vivo as antiinflammatory agents with minimal side effects.